Antibodies work by activating the complement cascade, preventing invading microorganisms from entering cells, or binding to a pathogen and marking it for destruction by immune cells. Now, Leo James and colleagues at the MRC-LMB in Cambridge have discovered a fourth method that works inside cells, providing a “last line of defense” against infection.

The ambush

James’ lab observed that antibodies can remain bound to adenovirus as it infects cells. The result sparked their curiosity, because they had previously shown that the intracellular protein TRIM21 binds to the Fc region of antibodies with higher affinity than any other antibody receptor in the body.

They found that TRIM21 adds ubiquitin to the adenovirus-antibody complex, targeting it for destruction by the proteasome. The finding “adds conceptually to the immune response,” says F1000 Member David Alpers.

The patents

TRIM21 only works if the virus doesn’t shed the antibody as it enters the cell. This means it should be effective against all nonenveloped viruses, such as rotaviruses and noroviruses, which cause diarrhea and gastroenteritis. James’ lab is in the process of cataloging which infections retain antibodies, and looking for other TRIM21-like proteins. They are also trying to develop novel antiviral therapies, having already applied for patents covering the use of synthetic TRIM21 to treat infections.